SU513628A3 - The method of obtaining the 15, 16 -methylene 4-estren-17-sols - Google Patents

Description

sterilizing the -oxy group and / or reducing the 3-keto group, esterifying the free oxy groups present in the molecule and isolating them with known techniques. Reduction of the 17-keto group can be accomplished by hydrogenation with a conventional catalyst, which, in the presence of hydrogen, causes reduction of the five-membered ketones. Complex hydrogen hydrides, for example sodium hydroborate, sodium hydroaluminate, sodium hydrotrimethoxoborate trimetry1-tert-butocoaluminate sodium . The reduction can also be carried out by a known method using an organometallic compound, for example, apkyl, alkenyl magnesium bromide. An organometallic compound used as a reducing agent can be formed Lvt situat and be used for reaction with 17-keto n, corresponding to the general formula. For example, for reaction with organometallic alkynyl compounds, the keto can be affected in a suitable solvent with alkyne, chloralkyl or alkadiine and alkali metal, preferably in the presence of a tertiary alcohol or ammonia under elevated pressure. Saturated 17cX1-alkynyl residues can be converted by hydrogenation to the appropriate 170 ° C alkenyl-or II (f-alkyl steroids. Hydrogenation is preferably carried out as follows: steroids with kenas (introduced with hydrogen in the presence of a hydrogenation catalyst, which can serve, for example, palladium or platinum oxide catalysts on carriers. The reduction of the 3-keto group is carried out by a known method, for example by hydrogenation with a conventional catalyst, which in the presence of hydrogen a causes the reduction of six-membered unsaturated ketones. The reduction can also be carried out with metal hydrides or complex hydride compounds, sodium hydrobromide, lithium hydrotrio-tert-butoxoaluminate. The esterification is carried out in a manner commonly used in chemistry to esterify steroidal alcohols. the hydroxy groups in position 3 are carried out by reacting the anhydride of the corresponding acid in the presence of a tertiary amine at room temperature. The etherification of 170 hydroxy groups is carried out, for example, by reacting this group with an acid anhydride in the presence of strong acids, for example p-toluenesulfonic acid, or a tertiary amine when heated. These etherification methods can also be used for u: l conversion of 3,17-dioxysteroids into diadylates. The keto - s; 11iitic group is cleaved by a known method using a mineral or organic acid, for example, perchloric or oxalic acid. We use the following examples i as the starting compounds 15cC, 6 s (-meg len- 17-oxo-5 (6) -i; 1H 5 i 10) -: .h: the grains are measured in the following way, OHHcaifflbiM in points L and V. L. 3,3- (2,2 -D 1methyl-1,3-propylene-dioxy) -18-metsh1-15D, 16 X-methylene-5 (6) or 5 (10) -estren-17-one . 46.2 g of natural 18-methyl-19-nor-4,16-pregnadien-3, 20-dione are heated in 2.5 d of benzene with 37.1 g of 2,2-dimesh1-1,3-propanediol and 2, 7 g p-toluenesulfonic acid for 6 hours with a water separator in the presence of phlegm. After cooling, the reaction solution is washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue obtained is chromatographed on silica gel to give, after recrystallization from diisopropyl ether, 28.6 g of natural 3.3- (2, 2-dimethyl-1, 3 fopylenedioxy) -18-methyl 19-nor-5.16-or 5 (10) , 16-pregnadien-20-she, so pl. MS-ISS C. UV Spectrum: E243-8530. 38.2 g of natural 3.3- (2, 2-dimethyl-1, 3-propylenedioxy) -18-methyl-19-nor-5,16-or 5 (10), 16-pregnadisn-20-one, dissolved in 229 ml of tetrahydrofuran, a solution of 29.2 g of tert.-potassium butylate in 343 ml of dimethylformamide and 57 ml of absolute tert-α-butanol, 22.9 ml of trimethylphosphite are added dropwise to a temperature of -20 ° C cooled to -20 ° C. Then continue stirring for 1 hour at –20 ° C and passing oxygen. The reaction solution is then mixed with slightly WATER acidified with acetic acid, the precipitate is filtered off, washed well with water, dissolved in methylene chloride and dried over sodium sulfate. The residue obtained after evaporation of 1 and the residue is chromatographed on silica gel, and after recrystallization from a mixture of diisoprolyl ether-methylene chloride, 15.5 g of natural 17-hydroxy-3,3- (2, 2-dimethyl-1, S-propylenedioxy) -18-methyl-19 are obtained. -nor - 5,15-or 5 (10), 15-pregnadien-20-one, t. pl. 202-214 ° C. 14.0 g of natural 17-hydroxy-3,3- (2, 2-dimethyl-l, 3-propylenedioxy) -18-methyl-19-nor-5,15-or 5 (10), 15-pregnadi- 20-it is dissolved in 140 ml of absolute tetrahydrofuran, mixed with 14.0 g of lithium tri-tert-butoxyalanate and kept at room temperature for 1 hour. The reaction solution is mixed with ice-cold water, acidified with dilute sulfuric acid and extracted with methylene chloride. The crude product obtained after drying and evaporation was chromatographed with n H of silica gel, and 13.0 g of natural 17,20-alioxy-3,3- (z, 2-dimethyl-1, 3-propilendaoxy) -18-methyl-19- nor-5,15-or. 5 (10), 15-pregnadnena 10.4 g of natural 17,20 $ -dioxy-3,3- (2 D - -dimethyl-l, 3 -lropylenedioxy) -18-methyl-19- -nor-5,15 -or 5 (10), 15-pregnadiene is heated in 185 ml of absolute ether (/ ethylene) and 185 ml of absolute ethylene glycol dimethyl ether with 16.8 ml of methylene iodide and 20, ti g of zinc-copper alloy for 5 hours in the presence of reflux. It is then diluted with methylene chloride, washed with a saturated solution of aluminum chloride and water, stirred over sodium sulfate and evaporated to dryness in vacuo. The chromatographic silica gel and receive. 20-dioxy-3,3- (2, 2-. Polymethyl-l, 3-propy lendioxy) -18-methyl-15 ° C, 16 ° C-methylene-19 nor-5-or 5 (10) -pregnen. 9.0 g of the obtained compound in 360 ml of methylene chloride is mixed with 27 g of the pyridine-chromic acid complex (prepared by converting chromium (yj} oxide into pyridium e and isolating the precipitated complex) and stirred for 3 hours at room temperature. The reaction solution is filtered and the filtrate is evaporated in vacuo to dryness. The residue is chromatographed on silica gel to obtain 3.9 g of natural 3.3- (2, 2-dimethyl-1, 3-proshsendioxy) -18-methyl-15 L, 16 sC-methylene-5- or 5 (10) -estren-17-one. B. 3.3- (2, 2 -Dimethyl-1, 3-propylene-di-oxy) -15L, 16 L-methylene-5 (6) -or 5 (10) -estre 5.0 g 19-nor –4.16-pregnadien-3,20-dione is heated in 250 ml of benzene with 4.0 g of 2,2-dimethyl-1,3-propanediol and 300 mg of p-toluenesulfonic acid for 2 hours with a water separator with a Y. reflux. t according to item A. After chromatography on silica gel, 4.9 g of 3.3- (2, 2-dimethyl-1, 3-propylene-dioxy) -19-nor-5.16-or 5 (10) are obtained, 16- pregnadien-20-one. UV spectrum: E2d - 9200. 5.0 g of the obtained compound is reacted with a solution of potassium tert-butylate, oxygen and trimellphosphite at -5 ° C, as described in paragraph A, and ends experience as indicated there. - After chromatography on silica gel and recrystallization from a mixture of diisopropyl ether-methylene chloride, 1.5 g of 17-hydroxy-3,3- (2, 2-dimethyl-1, 3-propylene dioxy) -) 9-nor-5,1,5 are obtained. -or .5 (10), 15-pregnadien - 20-she, so pl. 241-249 ° C. 44.5g 17-hydroxy-3,3- (2,2-dimethyl-1 3-propylenedioxy) -19-nor-5,15-or 5 (10), 15-pregnadien-20-one in 440 ml of absolute tetrahydrofuran they interact with 45 g of lithium tri-tert-butoxyalanate, as described in point A, I, and end the experiment, as indicated there. After chromatography on silica gel, 37.6 g of 17.20-dioxy-3, 3- (2, 2-dimethyl-G, 3-propylenedioxy) -19-nor-5,15-or 5 (10), 15-pregnadiene are obtained. . 35.6 g of the obtained compound are heated in 475 ml of absolute ether and 475 ml of absolute ethylene glycol dimethyl ether with 57.3 ml of methylene iodide and 71.2 g of zinc-copper alloy for 6.5 hours with stirring and refluxing. After the chromatography on silica gel, 17.7 g of 17,20-dioxy-3,3- - (2, 2-dimethyl - 1, 3-propylenedioxy) -15, 16L-methylene - 19-nor-5- or 5 (10) -pregnen. 17 g of the obtained compound in 1.35 ml of methylene chloride in B1H1 BCI interaction with 51 g of pyridine-chromic acid complex for i hour at room temperature and finish on iiyHKiy A. After chromatography on cJ iculele, 7.4 g of 3 3- (2, 2-dimepsh, 3 -propylene dioxy) -IScC, 16L-methylene-5-or 5 (10) -estrene - 17-one. The sample recrystallized from hexane is melted at 173-177 ° C. From ketals by a known method, one can prepare free oxo-compounds. Example 1. 12.0 g of natural 3,3- (2, 2-dimethyl-1, 3-propylene dioxy) -18-methyl-5 ° C, 16 (K-methylene-5-or 5 (10-estrene-17-one In 200 ml of absolute tetrahydrofuran is mixed with 12.0 g of lithium tri-tert-butoxyalanate and stirred for 1 hour at room temperature, then mixed with ice water, acidified with dilute sulfuric acid, extracted with methylene chloride and washed with methylene chloride phase until neutral. drying, evaporation and chromatography on silica gel afforded 3.3- (2, 2-dimethyl-1, 3-propylene-di-oxy) -18-methyl-15 ° (., - 16 X-methylene-5-sh1i 5 (10) -zst en-17 1-ol. Example 2. 11.5 g of natural 3.3- (2, 2-dimethyl-1, 3-propylene dioxy) -18-methyl-15X, 16 ° C methylene-5-or 5 (10 -estrene-17 -ol in 414 ml of methanol is heated with 8.3 g of oxalic acid in 83 ml for 2.5 hours if present and then poured into ice-cold water. The precipitate formed is filtered off and dissolved in methylene chloride. extrusion and evaporation of the residue is chromatographed on silica gel. 7.0 g of prio; 17/3-oxy-18-methyl- - i5 are obtained (X, 16L-methylene-4-estren-3-one. UV spectrum; 240 16200. Example 3. 2, OGZ, 3 - (2, 2-dimethyl-1,3-propylene dioxy), -methylene-5-or 5 (10) -estren-17-one in 30 ml of absolute tetrahydrofuran is reacted with 2.0 g of lithium tri-tert-butoxyalanate, as described in example 1, and the experiment of the same example is completed: 1.95 g of 3.3- (2, 2-dimethyl-G, 3-propylene-dioxy), 16 L-methylene-5-or 5 (10) estrene -17 / -ola. Example 4. 1.95 g3, 3- (2, 2-dimethyl-1, -propylene dioxy) -15 ° C, 16 ° C-methylene-5-ylt1 (10) -estrene-17/3 -ol in 70 ml of methanol is heated with 1.4 g of oxalic acid In 14 ml of water for 3 hours with reflux. At the end of the experiment conducted in Example 1 and after chromatography, silica gel gives 1.5 g of 17/3 -oxy-15L, BO-methylene-4-zstren-3 UV spectrum: E2 D-1T500 Example 5. 900 mg of magnesium chips in 13 ml of absolute tetrahydrofuran are brought into interaction with 2.93 ml of ethyl bromide to obtain tilmagnesium bromide. Under cooling, drop by drop in 26 ml of absolute tetrahydrofuran which res cut acetylene. TO

A solution of 900 mg of natural 3,3- (2, 2-dimethyl-1, 3-simple 1-dioxy) -18-methyl-5 i (, 1b1 C-methylene-5- or 5 (10) -estrene-17) is added to a solution of methyltin bromide. -on in 25 ml of absolute tetrahydrofuran and continue to stir for 3 hours at room temperature. Then the excess Grignard reagent is mixed with a saturated solution of ammonium chloride and the aqueous phase is extracted with ether. After drying and extracting, 910 mg of natural 3.3- (2, 2 - dimethyl-1, 3-propylene dioxy) -18 methyl-17i3C-ethyl-15-s, 16dC-methylene-5-or 5 (10) -estrene-17p-ol.

Example 6. 900 mg of naturally occurring 3,3- (2, 2-dimethyl-1, 3-propylenedioxy) -18-metnp-17dC-ethynyl-15 (L, 16 ° C-methylene 5- or 5 (10) -estrene- 17 p-ol in 10 ml of methanol is heated with 1.08 g of oxalic acid in 2.5 ml of water for 45 minutes under reflux, then diluted with ether, washed with water until neutral reaction, dried and evaporated to dryness in vacuo. on silica gel. After recrystallization from diisopropyl ether, 500 ml of natural 17 / J-oxy-18-methyl-17L-ethynyl-15L, 16L-methylene-4-estren-3-one are obtained, mp 189.5-191 WITH.

UV spectrum: 240 17200.

Example 7. 2.0 g of magnesium shavings are transformed into ethynyl magnesium bromide, as described in Example 5, mixed with 2.0 g of 3.3- (2, 2-dimethyl-1, 3-propylene endoxy) -15L, 16L-methylene-5 - or 5 (10) - -ES Fen-17-one in 20 ml of absolute tetrahydrofuran and stirred for 2.5 hours at room temperature. At the end of the work, 2.0 g of 3.3- (2, 2-dimethyl-, 3-propylenedioxy.si) -17L; 17/3-ola.

Example 8. 2.0 g of crude 3,3- (2, 2-dimethyl-1, 3-propylene-di-oxy) -17L-titinyl-CZL, 16L -methylene-5-or 5 (10) -estrene-17p -ol in 20 ml of methanol is mixed with 2.0 g of oxalic acid in 2.2 ml of water and heated for 2 hours in the presence of phlegm. The experiment is completed as described in Example 6. After chromatography on silica gel, after recrystallization of a mixture of methylene chloride diisopropyl ether, 1.2 g of 17 p -oxyn-P (ethynyl-15 ° C, 1-methylene-4-estren-3-one, t. mp 145-146 ° C.

UV spectrum: E-yjg-l OO.

Example 9. 5.0 g of natural 17 p, -oxy-18-methyl-15l, 1BOC-methylene-4-extremi-3-one in 20 ml of pyridine and 10 ml of acetic anhydride are kept for 18 hours at room temperature. Then it is poured into ice-water with stirring, the precipitate is filtered off and dissolved in methylene chloride. The methylene chloride phase is followed by. hence dilute hydrochloric acid, water, sodium bicarbonate solution and water. After drying and evaporation, 5.5 g of natural 17p, -acetoxy-18-methyl-15L, 16cC-methy / 1 and-4-estremol are obtained.

UV spectrum: 249- SO.

Example 10. 1.0 g 17 and -OXI-15L, 16oC-methylene-4-estren-3-one in 4 ml of pyridine is reacted with 2 ml of acetic anhydride, as described in example 9, and the experiment is completed as described there. After recrystallization from hexane, 820 mg of 17/3-acetoxy-15 (X., 16 ° C-methylene-4-estren-3-one) are obtained, mp 139.5-140.5 ° C.

UV spectrum: 239-1 000 Example 11. 600 mg of natural 17 p -oxy-18-methyl-17 L-ethynyl-15 (X, 16 L-methylene-4-β-estren-3-one is heated in 2 ml of acetic anhydride and 2 ml of pyridine for 10 hours in a stream of nitrogen in the presence of reflux. Then poured into ice water with stirring, the precipitated precipitate is filtered, washed with water and dried. To split the 3-enol acetate, it is added to 30 ml of methanol and heated for 15 minutes with 0 , 3 ml of concentrated hydrochloric acid under reflux. After precipitation with ice water, the precipitate is filtered, washed with water and dried. On silica gel, 510 mg of a natural 17p, - -acetoxy-18-methyl-17 (-ethynyl-15L, 16 ° C - methylene-4-estrhen-3-one) are obtained. The sample recrystallized from diisopropyl ether melts at 167.5-169. , 5 ° C.

UV spectrum:

Example 12. 500 mg of natural 17 / i, α-oxy-18-methyl-17 (α-ethynyl-15 ° C, 16 ° C-methylene-4-β-estren-3-it is heated for 10 hours in 2 ml of butyric acid and 2 ml pyridine in a stream of nitrogen at. Then the experiment was terminated as described in Example 11 and the 3-enol simple ether was resolved. After chromatography on silica gel, 450 mg were obtained

6 natural Pr-butyryloxy-18-methyl-17 ° C - α-ethynyl-15 ° C, 16L-metsh en-4-e (1Tren-3-one. The sample recrystallized from pentane melts at 118-122 ° C.

UV spectrum: 240 - 6900.

0

Example 13. 500 mg of natural 17p -oxy-18-methyl-17 X-ethynyl-15c., 16 Pts-methylene-4-β-estren-3-one is heated for 17 hours in 2 ml of enanthic anhydride and 2 ml of pyridine in a stream of nitrogen at 5 170 ° C. Then finish the experiment in example 11 and raschop ,. are 3-enol ether. Excess enanthic acid is removed by steam distillation. The product obtained after extraction with ether is chromatographed on silica gel to obtain 380 mg of prioic 17 (3-heptanoyloxy-18-methyl-

0 - 17l-ethynyl-15b, 16 (h-methylene-4-estren-3-ook as an oil.

UV spectrum: 249-17000.

Example 14. 400 mg of 17p -oxy-17 tf-ethynyl5-15L, 16 L-methylene-4-estren-3-one is converted into 2 ml of acetahydride and 2 ml of liridine, as described in example 11, and the experiment is terminated as described ibid. After chromatography on silica gel, 390 mg of 17 p-acetoxy-17 o (α-ethynyl-150 (, 16 f. 60 -methylene-4- :: stron-3-one) are obtained. 9 UV spectrum: Example 15. 150 mg 17p-oxy-17-X; -ethynyl-15glC, 16 cC-methylene-F-estren-3-one is converted into 1 ml of butyric anhydride and 1 ml of pyridine as described in example 11, and the experiment is completed as described there After chromatography on silica gel, 130 mg of 17 B-butyryloxy-PL-ethynyl-15L, 16 ° C methylene-4-estren-3-one are obtained UV spectrum: E239-17400. Example 16. 150 mg of 17p-hydroxy -17-ethynyl-15 OC, 16; -methylene-4-estren-3-one is converted into 1 ml of enanthic anhydride and 1 ml of pyridium a, as described in example 11, and the experiment is completed as described there. After chromatography on a silica gel, 140 mg of 17p -heptanoyloxy-17L-tinshl-15 ° C, 16 are obtained (CX-methylene-4-estren-3-one in oils. UV spectrum: 239. PRI me R 17. 250 mg of natural 17 p -hydroxy-18-methyl-17l-ethyn-15 ° C, 16-methnylene-4-extren-3-one in 20 ml of absolute tetrahydrofuran is mixed with 800 mg of lithium tri-tert-butoxy-alanate and interbeded for 1 hour at room temperature. Then it is poured into ice water with stirring, acidified with diluted acidic water, extracted with methylene chloride and washed with methylene chloride phase until neutral. After drying and melting, get 240 mg of the crude product. By recrystallization from diisopropyl ether, 140 mg of prnrodno, 3 p, 17 p-dnnox-18-methyl-17 ° (α-ethynyl -15 ° C, -16 ° C-methylen-4-estrene, mp 183-187 ° C are obtained. T. Example 18. 300 mg of 17 p -oxy-17L-ethynyl 15, 16 L-methylene-4-estren-3-one in 25: lp of absolute tetrahydrofuran is mixed with 950 mg of l :: ti-tri-tert.-butoxyalanate and from 1 hour at room temperature. The experiment of example 17 is completed. After chromatography on silica e, 250 mg of 3 / 3.17 / 3-dioxy-17 L-ethynyl-15 (, 16 ° C, methylene-4-estrene are obtained. At measure 19. 300mg 3 p, 17 p -dioxy-18-methyl-17 ° C - ethynyl-15 OC, 16 ° C - methylene-4- -Estrene is kept in 1 ml of pyridine with 0.5 ml of acetic anhydride for 18 hours at room temperature, then poured into ice-cold water with stirring, the precipitate is filtered off, washed with water and dried to obtain 320 mg of natural 17 p - -oxy-3 p - acetoxy-18-methyl-17 ° C - ethysh-15 ° C, 16 ° C - methylene-4-estrene, M.P. 117-118.5 C Example 11: 250 mg 3 p, 17/3-dioxy -17 (X ethynyl-15 7., 16 0 -methylene-4-estrina is converted into 1 ml of pyridine with 0.5 ml of acetic anhydride, as described in example 9, and the experiment is terminated as described there. 260 mg of 17 -thydroxy-3 p-acetoxy-17 ° C-epsil-15 ° C, 16 ° C-methylene -4-estrene are obtained. Example 21. 100 mg of natural 3 p, 17 p -dioxy-18-methyl-17 L-ethynyl-15 (X, 16L-methylene-4-estria is heated in 1 ml of pyridine and 1 ml of acetic anhydride for 10 hours in current nitrogen in the presence of reflux. Then poured on PS water into ice water, injected, the precipitate is filtered, washed with water and dried. After chromatography and the silica gel, 60 mg of natural 3 p, 17 p-dyethoxy-18-methyl-17CSPHT1HL-15 ° C are obtained, 16 L-mg-4-estrene. Example 22. 125 MHz p, 17 p-dioxy-17 (ethinyl-15 ° C, 16 cC-methylene-4-estrene is heated as in Example 21 and the experiment is completed as described in the same example. After chromatography on silica gel, 70 mg of 3 p, 17/3-diacetoxy-17 ° C-ethynyl 15 ° C, 16 L-methyLen-4-estrene are obtained. Example 23. 200 mg of natural 17 P-acetoxy-18-methyl- 17 L-ethynyl 15 ° C, 16 L-methylene-4-estren-3-one in 20 ml of absolute tetrahydrofuran is mixed with 670 mg of lithium tri-tert-butoxy alanate and stirred for 1 hour at room temperature. End the experiment in example 17. After chromatography 160 mg of natural 3/3 -oKc: i-17 p -acetoxn-18-methyl17 L-ethynyl-15 ° C, 16 L-methylene-4 estrene are obtained on silica gel. PRI mme R 2. 150 mg of 17 p-acetoxy-17 ethynyl-15 ° C, 16 cC-methylene-4-estren-3-one in 15 ml of absolute tetrahydrofuran is mixed with 500 mg of lithium tri-tert-itoxy-alanate and stirred 1 hour at room temperature. Finish work by example; 17. After chromatography on silica gel, 105 mg of 3 p -oxy-17 bC of acetoxy-17-ethynyl-15 cC, 16 cC -methylene4-estrene are obtained. EXAMPLE 25: 1.0 g of natural 3.3- (2, 2-dimethyl-11 3-: propylenedioxy) - 18-methyl-15 s, 16 ° C-meths-5-or 5 ( 10) -estr-17-one is dissolved in 30 ml of absolute tetrahydrofuran and introduced into the solution of Grignard reagent (prepared from 1 g of magnesium chips, 3.25 ml of ethyl bromide and 15 ml of absolute tetrahydrofuran) and kept at room temperature for 4 hours. The reaction mixture is then mixed with the above-mentioned ammonium chloride solution, the aqueous gas is separated and extracted with ether. The combined organic phases are washed with water, dried and concentrated. 950 mg of crude natural 3.3- (2 2-dime Tiui-l 3-propylenedloxy) -1y-methyl-B ° C ethyl 15 o (, 16 OC -methylene-5-or 5 (10) -estrene-ProL is obtained. Example 26. 300 mg of crude natural 3,3- (2, 2-dimethyl-1, 3-propylenedioxy) -18-methyl-17 L-ethyl-15cC, 6o-methylene-5-or 5 (10) estrene -17 o -ola is heated for 45 minutes in 10 ml of methanol with 300 mg of shavelic acid in 1.5 ml of water with reflux. The ont of Example 6 is completed. After chromatography on silica gel, 130 mg of natural 17 p -oxy-18-methyl-17 s are obtained: - ethyl-15 OC, 16 cC-methylene-4-estren-3-one. UV spectrum E240- 16900. Examber 27. Towards methyl lithium, prepared om of 185 mg lithium and 0.8.) ml of methyl iodine in 15 MJ. of absolute ether, 6/0 mg of transichlorethylene in 3 ml of absolute ether is added and stirring is continued for 1.5 hours at room temperature. 500 mg of natural 3.3- (22-dimetl-1 3-propylenedioxy) -18-methyl-15 (, 6 s -methylene-5- -or 5 (10) -estro-17-one in 20 ml of absolute toluene for 15 minutes and then 2.5 parts of the mixture are heated under reflux. The excess reagent is then decomposed while cooling with ammonium chloride solution, diluted with sulfur and washed with water until neutral. After welding, 520 mg of raw natural is obtained 3.3. - (2 2 dimethyl-1, 3-propylenedioxy) -18-methyl-17 (A. -chlorethynyl-15 L, 16 cC-methylene-5-or 5 (10) -estrene-I-dr. Example 28. 520 mg raw natures 3, 2-dimesh-1 -1, 3-propylenedioxy) -1 -methyl-17 p -chlorethynyl-15 s, 16 cC -methylene-5 or 5 (10) -estrates - 17 p -ol i 20 ml Methanol is heated for 45 minutes with 500 mg of oxalic acid in 2.5 ml of water in the presence of reflux. The experiment of Example 6 is completed. After chromatography on silica gel, 280 mg of natural 17 p -hydroxy-18-methyl-17 are obtained (CS-chloroethenyl-15 cC, 16-methylene-4-estren-3-one. UV spectrum: 240 17200. Example 29. 300 mg of natural 3.3- (2, 2-dimethyl-II, C-pronylenedioxy) -18-methl-17oC- Atinil-15L, 16 X.-methylene-5-or 5 (10) -estren-17 p -ol in 50 ml of benzene, which does not contain ti ofen. Hydrogenated with 200 mg of Lindlar catalyst to absorb two equivalents of hydrogen. The catalyst is filtered off and the solution is evaporated in vacuo to dryness. 300 mg of crude natural 3, 3- (21 2-D11methyl-1, 3-propylenedioxy) -18-methyl-17L-ethyl-15h, 1 6 s -methyl lei-5- or 5 (10) -estrone are obtained. 17 p - ol. Example 30. 500 mg of natural 17 p -oxy-18-methyl-15 (C. 16 L-methylene-4-estren-3-one in 15 ml of collidine is heated for 5 hours with 5 ml of lauric anhydride under nitrogen atmosphere at ki After the chromatography on silica gel, 392 mg of 17 | 3-dodecanoyl-18-methyl-15 °, 16-α-methylene-4-estrine-3-she in the form of slightly yellow colored are obtained. viscous oil. UV spectrum: E-, - 16600. Example 31. 150 mg of natural 3 p, 17 p - -dioxy-18-megyl-17 tf -egynyl-15L, -methylene-4-estrene is kept for 15 hours at room temperature with 1 ml of eianthanoic anhydride pyridine and 0.5 ml of pyridine. The experiment is completed in accordance with Example 19. 100 mg of natural 17/3 -oxy3 p-p; pthanoyloxy-8-methyl-17 CTC-ethynyl-15 CC, 16 L of miltilene-4-estrene in as an oil. Example 32. 250 mg of natural 3 p -oxy-17 p-acetoxy-18 methyl-17 cC-ethynyl-1 5c (16 ° C-methylene-4-estrene with 2.5 ml of collidine and 1.5 Caprylic acid anhydride MG is allowed to stand at room temperature for 18 hours. The experiment is terminated as described in Example 19. 180 mg of 17 A-aietoxy-3-octanoyloxy-8-methyl 17-6-ethynyl-15, 16c1-methylene 4-estrene-like oil is obtained. Example 33. In about 30 ml of liquid ammonia at (-80) - (- 60) ° C after the addition of traces of iron (111) nitrate, make 1.4 g of sodium in small pieces, and before each addition the blue color is expected to disappear. After addition of the alkali metal, 1,4-dichloro-butin-2 is slowly added dropwise and the mixture is stirred for 30 minutes. Then, 500 mg of natural 3.3 (2,2-dimethyl-1, 3-propylenedioxy) -18-methl15 (16, s-methylene-5-or 5 (10) -estren-17-it) in 10 ml of absolute tegrahydrofuran and pep eiivat 2 hours at i-40) C, then decompose with ammonium chloride and ammonia is evaporated at room temperature. The residue is taken up with methylene chloride, the solution is washed with water, dried and evaporated. 350 mg of 3, 3- (2 2-dimethyl-11 3-lylene di-dioxy) -18-methyl-17 (X-butadinyl-15L, methylene-5-or 5 (10) -estrine-17 p -ol are obtained Example 34. 350 mg of crude natural 3.3 (2, 2-dimedyl-, 3-propylenedioxy) -18-methyl-17 L-butadiyn-15 cl, 16 L-methylene-5- or 5 (10) -estrene -17 / 3-ol in 15 ml of methanol is heated 45 minutes with 350 mg of oxalic acid in 2 ml of water. The experiment of Example 6 is completed. After chromatography on silica gel, 150 mg of natural 17 p-hydroxy-18-methyl-17 L-butadiynyl are obtained -15 ° C 16 C-methylene-4-estren-3-one. UV spectrum: 239 16660. Example 35. 400 mg of natural 3, 3- (2,2-dimethyl-1, 3-propylenedioxy) -18-methyl- 17 s α-ethynyl-15 L, 16 ES-methylene-5-or 5 (10) -Es1ren-17 p -ol in 50 ml of benzene that does not contain thiophene, is hydrogenated with 250 ml of catalyst until it absorbs one equivalent of hydrogen. and evaporated in vacuo to dryness to obtain 350 mg of crude natural l, 3- (2, 2 - dimethyl-1, 3-propylenoxy) 88-methyl 17-ви1 (il-15, 16 L-methylene-5- or 5 (10) -17 /) -ola. Example 36. 350 mg of crude natural 3.3- - (2, 2-dimethyl-1, 3-propylenedioxy) -18-methyl-17 ° C VINIL-15L, 16 ° C methylene-5- or 5 (10) -estrene -17 p -ol in 5 ml of methanol is heated for 35 minutes with 350 mg of oxalic acid in 2.0 ml of water under reflux. The experiment is completed as described in Example 6. After chromatography on silica gel, 230 mg of natural 17 p -oxy-18-methyl-17 X -vinyl-1e cC, 16 L -methylene-4-β-estren-3-one are obtained. UV spectrum; E -, - 16500.

Claims (1)

13 claims The method of obtaining 15 L, 16 L -methylene-4 gasren-17 D-words of general formula 1 f fa U.-R, where R / is lower alkyl with 1-5 carbon atoms; B. - hydrogen atom or carboxylic acid with 1-15 carbon atoms;  an unsubstituted or substituted hydrogen atom, a chlorine atom, a saturated or unsaturated lower alkyl with 1 to 5 carbon atoms; X is an oxygen atom or a H.ORj group, in which RA is a hydrogen atom or a carboxylic acid residue with 1-15 carbon atoms, differing 513628 14 that 15l, 16 cC -methylene-17-oxo-5 (6) -shsh5 (10) -estrene of the general formula I where 8 has the above meaning; Y is preferably a keto group, protected as a ketal, is subjected to reduction, and the resulting compounds are either isolated or hydrogenated with a saturated 17 th alkyl, or the protective group is cleaved, or an 17 p -oxy group is etherified, {and / or 3-keto uppe is reduced, yugi ether), the free hydroxy groups present in the molecule and the desired products are obtained by known methods.